1. Field of the Invention
This invention relates to a method for decreasing lung damage in a host following the onset of gram negative septicemia/endotoxemia. The method of treatment comprises parenterally administering therapeutically effective amounts of antithrombin III and alpha-1-proteinase inhibitor.
The publications and other materials used to illuminate the background of the invention, and in particular cases, to provide additional details concerning its practice are incorporated herein by reference and listed at the end of the Specification in the form of a bibliography.
The adult respiratory distress syndrome (ARDS) is often associated with septicemia/endotoxemia, peritonitis, acute pancreatitis, fat emboli, aspiration pneumonitis, atelectasis, pulmonary emboli, pneumonia and other illnesses (1). Although an accurate accounting of the incidence of ARDS is unavailable, a government task force arrived at a conservative figure of at least 150,000 cases per year (2). At the present time, an effective treatment for ARDS associated with gram-negative sepsis still eludes the clinician. The serious impact of this on patient mortality is further emphasized by the observation that approximately two-thirds of patients dying in shock following resuscitation, or dying post-operatively die with ARDS (1).
Disseminated Intravascular Coagulation (DIC) is an early precursor associated with sepsis and shock leading to ARDS (3). It has been shown that DIC occurs quite early in sepsis, and that in fact it precedes the many other perturbations seen in the cardiovascular, metabolic, endocrine, and immunological systems (3). DIC is directly associated with a rapid consumption of clotting factors, as well as antithrombin-III (AT-III), a major inhibitor of the clotting system (4-9). Other studies have shown that when levels of AT-III decrease to below 70% of normal, the prognosis is grim (10). However, prophylaxis or pretreatment with high doses of AT-III (250 .mu./kg) has been shown to markedly increase survival in severely E. coli endotoxemic rats (3) and in fact to ameliorate indices of DIC in these endotoxemic rats and in the Klebsiella peritonitis rat model (11).
Margination and adhesion of polymorphonuclear leukocytes (PMN) to lung vessel endothelial cells, infiltration of PMN's into the lung extravascular space, and their subsequent release of elastase, oxygen free radicals, and other harmful substances also occurs early during the course of sepsis (13-17). Bronchoalveolar lavage (BAL) fluid from ARDS patients has been shown to contain PMN elastase (18), inactivated alpha-1-proteinase inhibitor (alpha-1-PI), and elastase-alpha-1-PI complexes (19).
In cases of impending sepsis and shock, prophylactic administration of AT-III and alpha-1-PI should be beneficial in preventing or at least attenuating the pulmonary damage associated with ARDS.
AT-III and alpha-1-PI should each provide protection within their respective range of function, and combining them results in an additive or synergistic benefit by: (1) inhibiting DIC and thus preventing reticuloendothelial system (RES) depression and allowing effective bacterial and/or microaggregate clearance; (2) inhibiting DIC and the subsequent plugging of lung microvessels by fibrin microaggregates; (3) inactivating neutrophil elastase and thus preventing lung vascular endothelial and alveolar tissue damage; and (4) protecting AT-III (20, 21) from inactivation by PMN elastase. The use of AT-III and alpha-1-PI combined for treatment of pulmonary dysfunction during inflammatory conditions such as gram-negative endotoxemia or septicemia has not been previously reported by others.
The present study was therefore completed to test the following hypotheses in the gram-negative endotoxemic sheep pulmonary dysfunction model: (1) alpha-1-PI supplementation alone limits the pulmonary damage; (2) AT-III supplementation alone limits the pulmonary damage; (3) the combination of AT-III and alpha-1-PI supplementation prevents or limits the pulmonary damage, and this efficacy is either additive or synergistic.
Results of the present study do not support our first hypothesis, weakly support our second hypothesis and strongly support our third.